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Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same

Inactive Publication Date: 2006-03-07
YUNGJIN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0151]In order that this invention be more fully understood, the following preparative and testing examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

Problems solved by technology

Necrotic cell death is harmful to tissues, inducing inflammation and etc.
However, quinoline compounds have not been previously identified as caspase-3 inhibitors.

Method used

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  • Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same
  • Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same
  • Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same

Examples

Experimental program
Comparison scheme
Effect test

preparation examples

Example 1

Synthesis of 2-[(2-Nitro-phenylamino)-methylene]-malonic acid diethyl ester (Compound of Formula 4)

[0152]To a solution of 2-nitroaniline (20 g, 144.8 mmol) dissolved in 400 ml of dry-ethanol in a 500 ml round bottom flask was added dimethylethoxymethylene malonate (34 g, 159.3 mmol). The solution was heated and refluxed for 6 hrs at 120° C. with stirring. The reaction was monitered by TLC (n-hexane / ethyl acetate=3 / 1). After completing the reaction and cooling to room temperature, the resulting precipate was collected by filtration, and the residue was washed three times with 100 ml of n-hexane to give 2-[(2-Nitro-phenylamino)-methylene]-malonic acid diethyl ester (31 g, 100.6 mmol, yield 69%).

[0153]1H NMR (300 MHz, CDCl3): δ=8.55 (d, 1H, —NHCHC(CO2CH2CH3)2, J=13.00 Hz), 8.28 (dd, 1H, aromatic H, J=1.25, 1.19 Hz), 7.68 (t, 1H, aromatic H, J=4.06 Hz), 7.52 (d, 1H, aromatic H, J=8.34 Hz), 7.23 (m, 1H, aromatic H), 4.42 (q, 2H, —NHCHC(CO2CH2CH3)2), 4.30 (q, 2H, —NHCHC(CO2CH2CH3...

example 2

Synthesis of 8-Nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (Compound of Formula 5)

[0154]A solution of 2-[(2-Nitro-phenylamino)-methylene]-malonic acid diethyl ester (10 g, 32.44 mmol) dissolved in 20 ml of diphenyl ether in a 250 ml round bottom flask was heated and refluxed for 5 hrs at 280° C. with stirring. The reaction was monitered by TLC (n-hexane / ethyl acetate=3 / 1). After completing the reaction and cooling to room temperature, 200 ml of diethylether was added to the mixture and the resulting precipitate was collected by filtration, and the residue was washed with 200 ml of diethyl ether to give 8-Nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (6.5 g, 19.08 mmol, yield 59%).

[0155]1H NMR (300 MHz, CDCl3): δ=11.40 (s, 1H, —NHCH—), 8.88 (d, 1H, —NHCH—, J=7.17 Hz), 8.69 (d, 2H, aromatic H, J=6.84 Hz), 7.56 (t, 1H, aromatic H, J=4.06 Hz), 4.42 (q, 2H, —CH2CH3), 3.39 (t, 3H, —CH2CH3, J=7.08 Hz)

example 3

Synthesis of 8-nitro-4-chloro-quinoline-3-carboxylic acid ethyl ester (Compound of Formula 6)

[0156]To a solution of 8-Nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10 g, 38.14 mmol) in 100 ml of thionyl chloride in a 250 ml round bottom flask was added a catalytic amount of 200 ul of dimethyl acetamide. The mixture was heated and refluxed for 2 hrs with stirring. The reaction was monitered by TLC (n-hexanelethyl acetate=3 / 1). After completing and cooling to room temperature, thiony chloride was removed under vacuum and 100 ml of water was added. The residue was extracted three times with 100 ml of ethyl acetate each time and the organic layer was dried over magnesium sulfate and filtrated. The residue was purified by column chromatography (hexan / ethyl acetate=3 / 1) to give 8-nitro-4-chloro-quinoline-3-carboxylic acid ethyl ester (9.5 g, 33.85 mmol, 89%)

[0157]1H NMR (300 MHz, CDCl3) δ=9.35 (s, 1H, —N═CH—), 8.67 (d, 1H, aromatic H, J=9.38 Hz), 8.17 (t, 1H, aromatic H...

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Abstract

The present invention relates to new quinoline derivatives of formula (1) or their pharmaceutically acceptable salts with caspase-3 inhibitory activity and their preparation methods, wherein R2 is H; halogen; C1-6alkyl; C1-6 alkoxy; C1-6 alkoxyalkyl; or C3-6cycloalkyl; R1 is formula (a); —CN; or formula (b); R is H; C6-14aryl unsubstituted or substituted by halogen, C1-6 alkyl, C1-6 alkoxy or amino; 5–15 membered heterocyclic group unsubstituted or substituted by halogen, C1-6 alkyl, C1-6 alkoxy or amino; or —(CH2)n—CHR4R5. The present invention relates to a pharmaceutical composition for treating caspase-associated diseases by inhibiting the activity of caspase-3 which comprises the compound of formula (1) or its pharmaceutically acceptable salt.

Description

[0001]This patent application claims the benefit of priority from Korean Patent Application No. 10-2002-0023838 filed Apr. 30, 2002 through PCT Application Serial No. PCT / KR03 / 00875 filed Apr. 30, 2003, the contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to caspase-3 inhibitors. Specifically, the present invention relates to novel quinoline derivatives or their pharmaceutically acceptable salts as caspase-3 inhibitors, their preparation methods and pharmaceutical compositions comprising the same.BACKGROUND OF THE INVENTION[0003]Control of cell numbers in mammals is believed to be determined, in part, by a balance between cell proliferation and cell death. One form of cell death, sometimes referred to as necrotic cell death, is typically characterized by a pathologic form of cell death resulting from some trauma or cellular injury. Necrotic cell death is harmful to tissues, inducing inflammation and etc. In cont...

Claims

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Application Information

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IPC IPC(8): C07D215/38A61K31/47C07D215/44C07D215/46A61K31/4706A61K31/4709A61K31/5377A61P9/08A61P19/00A61P19/02A61P21/04A61P25/08A61P25/14A61P25/16A61P25/28A61P31/18A61P43/00C07D215/42C07D215/54C07D401/12C07D405/12C07D409/12
CPCC07D215/42C07D215/44C07D409/12C07D401/12C07D405/12C07D215/54A61P19/00A61P19/02A61P21/04A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P31/18A61P43/00A61P9/08
Inventor KIM, SUNG-GYUJUNG, YOON SUNGKONG, JAE YANGPARK, WOO KYU
Owner YUNGJIN PHARM CO LTD
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